In preliminary studies we have demonstrated a potent inhibition of erythrocyte membrane Ca-stimulated-ATPase (Ca-ATPase) by zinc. Zinc inhibition of Ca-ATPase at concentrations down to 10 micronM has been shown by both inhibition in a Ca-ATPase (Pi) assay system and by inhibition of phosphorylation at the site of the Ca-ATPase protein bands in SDS-PAGE. In further preliminary work we have demonstrated zinc inhibition on Ca-ATPase activity from platelets. This work on a possible molecular effect of zinc on membranes is a follow-up to our earlier demonstration of an antisickling effect of zinc both in vitro and in vivo. In the laboratory, zinc at low concentrations improves sickle red cell filterability. In patients wich sickle cell anemia, oral zinc therapy has reduced the count of irreversibly sickled cells (ISCs) in the circulating blood. ISCs are membrane-damaged cells. These effects occur at such low concentrations of zinc that we have postulated a membrane effect of zinc as opposed to a hemoglobin effect. In other preliminary studies, zinc has been shown to have an ATP-preserving effect during prolonged incubations of red cells. This observation led to study of zinc effects on Ca-ATPase because this enzyme is capable of rapid hydrolysis of ATP in the presence of increased calcium levels. In the most recent work involving studies of zinc and a series of other drugs, we have found a positive relationship between red cell membrane expansion, inhibition of an activator (calmodulin) of Ca-ATPase and other enzymes, and certain classes of therapeutic action. Thus zinc, phenothiazines, tricyclic antidepressants, local anesthetics, and several types of cardiac antiarrhythmics all share the properties of membrane expansion and calmodulin inhibition. In the proposed work we plan to carry out further studies on these interrelationships.